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Therapy-induced senescence promotes breast cancer cells plasticity by inducing Lipocalin-2 expression

Morales-Valencia, Jorge; Lau, Lena; Martí-Nin, Teresa; Ozerdem, Ugur; David, Gregory
The acquisition of novel detrimental cellular properties following exposure to cytotoxic drugs leads to aggressive and metastatic tumors that often translates into an incurable disease. While the bulk of the primary tumor is eliminated upon exposure to chemotherapeutic treatment, residual cancer cells and non-transformed cells within the host can engage a stable cell cycle exit program named senescence. Senescent cells secrete a distinct set of pro-inflammatory factors, collectively termed the senescence-associated secretory phenotype (SASP). Upon exposure to the SASP, cancer cells undergo cellular plasticity resulting in increased proliferation, migration and epithelial-to-mesenchymal transition. The molecular mechanisms by which the SASP regulates these pro-tumorigenic features are poorly understood. Here, we report that breast cancer cells exposed to the SASP strongly upregulate Lipocalin-2 (LCN2). Furthermore, we demonstrate that LCN2 is critical for SASP-induced increased migration in breast cancer cells, and its inactivation potentiates the response to chemotherapeutic treatment in mouse models of breast cancer. Finally, we show that neoadjuvant chemotherapy treatment leads to LCN2 upregulation in residual human breast tumors, and correlates with worse overall survival. These findings provide the foundation for targeting LCN2 as an adjuvant therapeutic approach to prevent the emergence of aggressive tumors following chemotherapy.
PMID: 35953598
ISSN: 1476-5594
CID: 5287202

Macrophage density is an adverse prognosticator for ipsilateral recurrence in ductal carcinoma in situ

Darvishian, Farbod; Wu, Yinxiang; Ozerdem, Ugur; Chun, Jennifer; Adams, Sylvia; Guth, Amber; Axelrod, Deborah; Shapiro, Richard; Troxel, Andrea B; Schnabel, Freya; Roses, Daniel
INTRODUCTION/BACKGROUND:There is evidence that supports the association of dense tumor infiltrating lymphocyte (TILs) with an increased risk of ipsilateral recurrence in ductal carcinoma in situ (DCIS). However, the association of cellular composition of DCIS immune microenvironment with the histopathologic parameters and outcome is not well understood. METHODS:We queried our institutional database for patients with pure DCIS diagnosed between 2010 and 2019. Immunohistochemical studies for CD8, CD4, CD68, CD163, and FOXP3 were performed and evaluated in the DCIS microenvironment using tissue microarrays. Statistical methods included Fisher's exact test for categorical variables and the two-sample t-test or the Wilcoxon Rank-Sum test for continuous variables. RESULTS:The analytic sample included 67 patients. Median age was 62 years (range = 53 to 66) and median follow up was 6.7 years (range = 5.3 to 7.8). Thirteen patients had ipsilateral recurrence. Of all the clinicopathologic variables, only the DCIS size and TIL density were significantly associated with recurrence (p = 0.023 and 0.006, respectively). After adjusting for age and TIL density, only high CD68 (>50) and high CD68/CD163 ratio (>0.46) correlated with ipsilateral recurrence (p = 0.026 and 0.013, respectively) and shorter time to recurrence [hazard ratio 4.87 (95% CI: 1.24-19, p = 0.023) and 10.32 (95% CI: 1.34-80, p = 0.025), respectively]. CONCLUSIONS:macrophage density and CD68/CD163 ratio also predict a shorter time to recurrence.
PMID: 35489232
ISSN: 1532-3080
CID: 5217782

SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling

Fedele, Carmine; Li, Shuai; Teng, Kai Wen; Foster, Connor J R; Peng, David; Ran, Hao; Mita, Paolo; Geer, Mitchell J; Hattori, Takamitsu; Koide, Akiko; Wang, Yubao; Tang, Kwan Ho; Leinwand, Joshua; Wang, Wei; Diskin, Brian; Deng, Jiehui; Chen, Ting; Dolgalev, Igor; Ozerdem, Ugur; Miller, George; Koide, Shohei; Wong, Kwok-Kin; Neel, Benjamin G
KRAS is the most frequently mutated human oncogene, and KRAS inhibition has been a longtime goal. Recently, inhibitors were developed that bind KRASG12C-GDP and react with Cys-12 (G12C-Is). Using new affinity reagents to monitor KRASG12C activation and inhibitor engagement, we found that an SHP2 inhibitor (SHP2-I) increases KRAS-GDP occupancy, enhancing G12C-I efficacy. The SHP2-I abrogated RTK feedback signaling and adaptive resistance to G12C-Is in vitro, in xenografts, and in syngeneic KRASG12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). SHP2-I/G12C-I combination evoked favorable but tumor site-specific changes in the immune microenvironment, decreasing myeloid suppressor cells, increasing CD8+ T cells, and sensitizing tumors to PD-1 blockade. Experiments using cells expressing inhibitor-resistant SHP2 showed that SHP2 inhibition in PDAC cells is required for PDAC regression and remodeling of the immune microenvironment but revealed direct inhibitory effects on tumor angiogenesis and vascularity. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional potential combination strategies.
PMID: 33045063
ISSN: 1540-9538
CID: 4632492

Upgrade Rate of Intraductal Papilloma Diagnosed on Core Needle Biopsy in a Single Institution

Lin, Lawrence Hsu; Ozerdem, Ugur; Cotzia, Paolo; Lee, Jiyon; Chun, Jennifer; Schnabel, Freya; Darvishian, Farbod
The management of intraductal papilloma (IDP) diagnosed on core needle biopsy (CNB) is controversial due to the variable upgrade rates to breast carcinoma (BC) on subsequent surgical excision reported in the literature. The purpose of our study was to investigate the upgrade rate of IDP diagnosed on CNB to BC in subsequent surgical excision and the impact of clinical, pathologic and radiologic variables. This is a retrospective cohort of all women who had a diagnosis of IDP on a CNB between 2005 and 2018 in a tertiary academic center with subsequent surgical excision. Upgrade was defined as ductal carcinoma in situ (DCIS) and invasive carcinoma on surgical excision. Statistical analyses included Pearson's chi-square, Wilcoxon rank-sum and logistic regression. A total of 216 women with IDP in a CNB were included. Nineteen patients (8.8%) upgraded to BC in the overall cohort, including 14 DCIS and 5 invasive carcinomas. An upgrade rate of 27% was found in atypical IDP (14 of 51 cases), while only 3% of pure IDP upgraded to BC (5 of 165 cases). Older age (>53 years) at time of biopsy (OR=1.05, 95%CI 1.01-1.09, p=0.027) and concomitant atypical ductal hyperplasia (ADH) (OR=9.69, 95%CI 3.37-27.81, p<0.0001) were significantly associated with upgrade. Our results support surgical excision of IDP on CNB when associated with ADH or diagnosed in women older than 53 years of age. The low surgical upgrade rate of 3% for pure IDP on CNB in younger women should be part of the management discussion.
PMID: 33159966
ISSN: 1532-8392
CID: 4662082

The diagnostic utility of EZH2 H-score and Ki-67 index in non-invasive breast apocrine lesions

Vougiouklakis, Theodore; Belovarac, Brendan J; Lytle, Andrew; Chiriboga, Luis; Ozerdem, Ugur
In diagnostic breast pathology, there is no reliable applicable immunostain to help discern atypical and in situ apocrine lesions from benign apocrine tissue. At present, the diagnosis of non-invasive apocrine lesions remains challenging with current diagnoses rendered based on discrete morphologic characteristics on conventional hematoxylin and eosin staining. Interobserver variability is significant even among subspecialists partly due to lack of adjuvant diagnostic immunohistochemical stains. Herein, we set to elucidate the potential utility of EZH2 and Ki-67 immunostains as tangible tools in non-invasive apocrine proliferations. A cohort of apocrine breast lesions [Benign apocrine hyperplasia (BAH), n = 10; Atypical apocrine hyperplasia (AAH), n = 16; Apocrine ductal carcinoma in situ (ADCIS), n = 12] were subjected to EZH2 immunostaining and analyzed via H-scoring of nuclear expression. Mean H-scores for EZH2 progressively increased from BAH (23.5), to AAH (47.4) and ADCIS (196.4), and showed a significant difference utilizing the Kruskal-Wallis test (p < 0.0001). Further interrogation of Ki-67 demonstrated incremental expression from BAH to AAH and ADCIS at 1.6 %, 4.7 % and 24.7 %, respectively (p < 0.0001, Kruskal-Wallis test), suggesting an association with increased proliferation. Our results demonstrate that a combination of EZH2 and Ki-67 immunostaining may be employed in differentiating among challenging apocrine breast lesions and suggest a putative diagnostic utility for EZH2 and Ki-67 in non-invasive apocrine breast lesions.
PMID: 32825929
ISSN: 1618-0631
CID: 4574932

Pathologic Evaluation of Breast Tissue From Transmasculine Individuals Undergoing Gender-Affirming Chest Masculinization

Hernandez, Andrea; Schwartz, Christopher J; Warfield, Dana; Thomas, Kristen M; Bluebond-Langner, Rachel; Ozerdem, Ugur; Darvishian, Farbod
CONTEXT.—/UNASSIGNED:Bilateral mastectomy for chest masculinization is one of the gender-affirming procedures for transmasculine individuals. OBJECTIVE.—/UNASSIGNED:To optimize gross handling protocols and assess histopathologic findings in transmasculine breast tissue specimens. DESIGN.—/UNASSIGNED:We identified all gender-affirming mastectomies from 2015 to 2018. We sequentially identified reduction mammoplasty (RM) cases for macromastia from the same period as control. Significant findings were defined as atypical ductal or lobular hyperplasia (ADH, ALH), ductal or lobular carcinoma in situ (DCIS, LCIS), or invasive carcinoma. RESULTS.—/UNASSIGNED:Significant findings were present in 6 of 211 gender-affirming mastectomies (2.8%) as follows: ADH (n = 5) and LCIS together with ALH (n = 1). By comparison, 19 of 273 RM specimens (7%) yielded significant findings as follows: ALH (n = 11), ADH (n = 4), LCIS (n = 2), DCIS (n = 1), and invasive lobular carcinoma (n = 1). In the gender-affirming group, 142 transmen underwent androgen therapy before surgery, of whom 2 had significant pathologic findings. Thirty and 41 individuals had a family history of breast cancer in the gender-affirming and RM group, of whom 1 and 3 individuals had significant pathologic findings, respectively. CONCLUSIONS.—/UNASSIGNED:Our study demonstrates that we handle transmasculine mastectomy specimens by examining 2.8 times more slides on average than for RMs, with a 2.5 times lower rate of significant pathologic findings. Prior family history of breast cancer or the use of androgen therapy before surgery in gender-affirming individuals did not increase the risk of identifying significant breast lesions. We recommend submitting 4 tissue blocks per mastectomy for individuals undergoing gender-affirming breast surgery.
PMID: 31816268
ISSN: 1543-2165
CID: 4234122

Intraoperative evaluation of the nipple/subareolar tissue during nipple sparing mastectomy: Accuracy, pathological correlation and clinical significance [Meeting Abstract]

Serrano, A; Darvishian, F; Ozerdem, U; Nimeh, D; Cotzia, P; Gordin, S
Background: Intraoperative evaluation of the nipple/subareolar tissue (N/SAT) has been used by surgeons to assess for occult nipple involvement by malignancy and guide the decision-making process for nipple preservation during nipple sparing mastectomies (NSM). The aim of our study is to evaluate significance and accuracy of frozen section (FS) results compared to final pathology/permanent sections.
Design(s): We retrospectively reviewed records of patients that underwent NSM with FS of the N/SAT from 2014 to 2018. Positive FS or final pathology results include atypical hyperplasia, in situ and invasive carcinoma.
Result(s): Over a 5-year period a total of 339 NSM cases utilized FS to evaluate the N/SAT. Of the total 339 cases, 85(25%) were prophylactic and 254(75%) were therapeutic mastectomies. All 85 prophylactic mastectomies were negative (benign) on FS and final diagnosis. Among 254 therapeutic mastectomies, 217(85.4%) showed negative (benign) intraoperative FS with concordant benign final pathology; 22(8.7%) showed positive intraoperative FS with concordant positive final pathology; 15(5.9%) were false negative (benign) on FS and positive on final permanent sections (figure 1). Positive results consisted of atypical ductal or lobular hyperplasia (5, 27.8%), in situ ductal or lobular carcinoma (11, 61.1%) and invasive carcinoma (1, 5.6%). One false positive case showed "atypical intraductal proliferation" at FS and was diagnosed as intraductal papilloma on final pathology; the nipple was not removed at the time of surgery. Of the 37 cases with positive final nipple pathology, 14(37.8%) had intraoperative resection of the nipple/areola complex (NAC), 9(24.3%) required an additional surgery for removal of NAC and 13(35.1%) had no additional procedures performed. Residual pathology was identified in 9(39.1%) of the resected NAC. In our patient cohort frozen section diagnosis has a sensitivity of 58.3%, specificity of 99.5%, positive predictive value (PPV) of 95.5% and negative predictive value (NPV) of 93.5%. (Figure presented)
Conclusion(s): Intraoperative evaluation of the N/SAT is highly accurate (93.7%) and specific (99.5%) test that prevented additional surgical intervention in 8.7% of therapeutic mastectomies. At the same time, surgeons should be aware of the low/moderate sensitivity of intraoperative FS, which may be explained by processing artifacts, sampling or cautious approach not to overcall the FS findings
ISSN: 1530-0285
CID: 4471162

Insight into utility and impact of immunohistochemistry in evaluating microinvasion in breast core needle biopsies [Meeting Abstract]

Roychoudhury, S; Ozerdem, U; Warfield, D; Oweity, T; Levine, P; Hernandez, O; Darvishian, F
Background: Diagnosis of microinvasion (MI) in breast core needle biopsy (CNB) can be challenging particularly in a background of carcinoma in situ (CIS) involving sclerosing lesion with periductal fibrosis and lymphocytic infiltrate. Immunohistochemical stains (IHC) for myoepithelial cells aid in confirming MI. Surgical management of MI deviates from CIS as the former includes sentinel lymph node biopsy (SLNB) while the latter typically includes SLNB only when total mastectomy (TM) is planned. We investigated the utility of IHC in diagnosing MI in our CNBs and its impact on final histopathology on surgical excision.
Design(s): We conducted a search for cases of CIS with foci suspicious for MI, in which IHC for calponin and p63 was used to confirm MI (defined as invasive carcinoma <=1 mm) between January 2010 and June 2019. CIS included ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). MI cases diagnosed based on routine histology were also collected for the same time period. Only cases with follow up excision data were included. Cases with synchronous invasive carcinoma were excluded. Clinicopathologic data including age, size, laterality, resection type, SLNB status and biomarker profiles were compared. Graphpad Prism software was used for statistical analysis.
Result(s): We identified 106 cases of CIS (102 DCIS, 4 LCIS), where IHC was used to confirm MI (MI-IHC hereafter). Mean age was 58 years. Of the 106 cases MI-IHC was identified in 24 cases (23%). See table. All 24 MI-IHC cases had SLNB (100%). Of the 82 CIS cases, 39 had SLNB (48%). Relative risk of finding invasive carcinoma/MI on resection in MI-IHC was 1.8 (p=0.03) compared to CIS. There was no correlation between the biomarker profile with the resection outcome in either CIS (p=0.5, Fisher's exact test) or MI-IHC cases (p=3.4, Chi-square test). We identified 7 cases of MI, diagnosed on routine histology without IHC, of which 5 (71%) had invasive carcinoma/MI and 2 (29%) had CIS or no residual carcinoma on resection. Mean size of invasive carcinoma and CIS on resection in this group was 11 mm and 25 mm, respectively. The resection outcome between MI-IHC and MI based on routine histology was not significant (p=0.6). (Table presented)
Conclusion(s): IHC helped diagnose MI in CNB for CIS in 23% of cases. Compared to CIS, the diagnosis of MI-IHC carried a relative risk of 1.8 in finding invasive carcinoma/MI on resection. There was no difference in the significance of the method used for the diagnosis of MI
ISSN: 1530-0285
CID: 4471202

Mediator complex (MED) 7 is downregulated in high grade ductal carcinoma in situ (DCIS) [Meeting Abstract]

Belovarac, B; Vougiouklakis, T; Ozerdem, U
Background: The Mediator Complex (MED) is a large multi-subunit protein which interacts directly with RNA Polymerase II and transcription factors for general regulation of protein expression. Recently, Mediator Complex 7 (MED7) has been shown to be underexpressed in high grade invasive mammary carcinomas in comparison to lower grade invasive carcinomas. No study has yet investigated the expression of MED7 in ductal carcinoma in situ (DCIS). In our study, we set out to evaluate the biological significance of MED7 in DCIS.
Design(s): MED7 immunostaining was performed with a rabbit monoclonal antibody (EPR15410, Abcam- Ab187146, Cambridge, UK). The H-score method was utilized for quantifying MED7 nuclear expression in DCIS. This method combines nuclear staining intensity and the percentage of positive cells. Staining intensity (0-3) is multiplied by percentage of positive DCIS cells (0-100) leading to the H-score, with a range of 0-300 for each case. We investigated breast core biopsies with DCIS; 20 were high grade, 14 were intermediate grade, and 15 were low grade. The hormone receptor status of each case was also recorded. GraphPad PRISM 7.0 software was used for statistical analysis.
Result(s): The mean H-Score for high grade DCIS cases was 146, intermediate grade was 219, and low grade was 228 (p <0.0001, Kruskal-Wallis test). The mean H-score for high grade DCIS cases was significantly lower than that of low and intermediate grade DCIS (p <0.0001 and p = 0.0004, respectively, Dunn's test). The MED7 H-Score was significantly lower in ER negative cases compared to that seen in ER positive cases (p <0.0001). Area under the curve (AUC) in the ROC curve for MED7 H-Scores in high grade versus non-high grade DCIS cases was 0.9276 (p <0.0001). (Table presented)
Conclusion(s): Our results suggest that MED7 expression is significantly down regulated in high grade and ER-negative DCIS cases, thus implying a significant biological role of MED7 in the progression of DCIS. Taken together, our data establishes MED7 H-score as a tangible tool for evaluating high grade DCIS. Further studies are underway to establish a practical cut-off value for the MED7 H-Score for high grade DCIS. We believe that these important early steps investigating MED7 are crucial in clarifying its important role in the development and progression of breast and other cancers
ISSN: 1530-0285
CID: 4472602

Mediator Complex (MED) 7 is Downregulated in High Grade Ductal Carcinoma In Situ (DCIS) [Meeting Abstract]

Belovarac, Brendan; Vougiouklakis, Theodore; Ozerdem, Ugur
ISSN: 0023-6837
CID: 5525382