Rb deletion in mouse mammary progenitors induces luminal-B or basal-like/EMT tumor subtypes depending on p53 status

Jiang, Zhe; Deng, Tao; Jones, Robert A.; Li, Huiqin; Herschkowitz, Jason I.; Liu, Jeff C.; Weigman, Victor; Tsao, Ming‐Sound; Lane, Timothy F.; Perou, Charles M.; Zacksenhaus, Eldad

doi:10.1172/jci41490

Cited by 135 publications

(137 citation statements)

References 78 publications

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“…Although it has been previously reported that persons with heritable RB were at increased risk of breast cancer, 34 only recently was this finding supported by animal models. 35 As shown here, the RB pathway is compromised in DCIS lesions as detected by elevated p16ink4a expression. Although this finding has been previously described, 6,24 here, we demonstrate that the p16ink4a-positive lesions that exhibit elevated Ki-67 are indeed deficient for RB protein, and such DCIS cases exhibit gene expression profiles indicative of RB loss.…”

Section: Discussionsupporting

confidence: 56%

Association of RB/p16-Pathway Perturbations with DCIS Recurrence

Witkiewicz

Rivadeneira

Ertel

et al. 2011

The American Journal of Pathology

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The prevalence of ductal carcinoma in situ (DCIS) diagnoses has significantly increased as a result of active radiographic screening. Surgical resection and hormone and radiation therapies are effective treatments, but not all DCIS will progress to invasive breast cancer. Therefore, markers are needed to define tumors at low risk of recurrence and progression that can be treated by surgery alone rather than by adjuvant therapies. Initial analyses indicate that retinoblastoma (RB)-pathway perturbations occur at high frequency in DCIS and mirror the molecular alterations observed in invasive breast cancer. Particularly, the elevated expression of p16ink4a in DCIS was associated with loss of RB function and estrogen receptor-negative biology. Furthermore, high expression of p16ink4a in conjunction with Ki-67 was associated with increased risk of DCIS recurrence and progression to invasive disease in multivariate analyses. These data are consistent with a functional role for RB in modulating the invasive behavior of mammary epithelial cells. The tissue microenvironment is particularly relevant to the behavior of DCIS, and, surprisingly, elevated expression of p16ink4a in nonproliferative stroma was observed in a substantial fraction of cases. In this tissue compartment, p16ink4a expression was strongly associated with disease recurrence, independent of standard histopathologic features. Together, the data herein describe dual aspects of RB-pathway biology that are associated with disease recurrence through the epithelial or stromal compartment of DCIS. (Am J Pathol

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Section: Discussionsupporting

confidence: 56%

Association of RB/p16-Pathway Perturbations with DCIS Recurrence

Witkiewicz

Rivadeneira

Ertel

et al. 2011

The American Journal of Pathology

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show abstract

“…This model highlighting a role for RB and p53 in stem/progenitor cell populations is compatible with other mouse models of human cancers associated with loss of RB and p53 function, including in the blood compartment, in bones, in the retina and in the mammary epithelium. [35][36][37][38][39] However, the identity of potential neuroendocrine cell progenitors in adult lung tissue has not yet been established.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the cell of origin for small cell lung cancer

et al. 2011

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“…Deletion of Rb via two different MMTV-Cre lines induced focal acinar hyperplasia with squamous metaplasia. 70 These lesions progressed into histologically diverse mammary tumors. RNA microarray analysis revealed that the Rb doublemutant mice.…”

Section: Consequences Of Rb Deletion In the Mammary Glandmentioning

confidence: 99%